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Original Research |
1 Division of Pulmonary & Critical Care Medicine, Department of Internal
Medicine, Chang Gung Memorial Hospital-Kaohsiung Medical Center, Chang Gung
University College of Medicine, Taiwan, ROC.
2 Division of Infectious Diseases, Department of Internal Medicine, Chang Gung
Memorial Hospital-Kaohsiung Medical Center, Chang Gung University College of
Medicine, 123, Ta Pei Rd., Niao Sung Hsiang, Kaohsiung Hsien 833, Taiwan,
ROC.
3 Department of Nuclear Medicine, Chang Gung Memorial Hospital-Kaohsiung Medical
Center, Chang Gung University College of Medicine, Taiwan, ROC.
4 Present address: Chest Division, Department of Internal Medicine, E-Da
Hospital, Taiwan, ROC.
Received April 30, 2006;
accepted after revision October 31, 2006.
Address corespondence to J.-W. Liu
(88b0{at}adm.cgmh.org.tw).
Abstract
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SUBJECTS AND METHODS. Each enrolled patient had chest radiographic, microbiologic, 67Ga imaging, and semiquantitation of sputum acid-fast bacillus (AFB) assessments before and at the third and sixth months after receiving anti-TB chemotherapy. The burden of pulmonary M. tuberculosis (presumably, in proportion to the semiquantitation of AFB in sputum) and the intensity of 67Ga citrate uptake in the lung at each synchronized assessment were regarded as a paired variable. Odds ratios were obtained from odds (derived using generalized estimating equations) in favor of higher pulmonary 67Ga uptake in differing scores of semiquantitation of sputum AFB. Linear trend for pulmonary 67Ga citrate uptake corresponding to varied pulmonary M. tuberculosis burdens was assessed using contrast analysis of their odds ratios.
RESULTS. Thirty patients (24 men and six women) with pulmonary TB were enrolled. Eighty-six paired semiquantitations of sputum AFB-67Ga-scintigraphic studies were collected. Twenty-six patients were cured of their pulmonary TB. The pulmonary 67Ga uptake increased in proportion to the higher score of semiquantitation of sputum AFB (p = 0.009, for trend).
CONCLUSION. In patients with pulmonary TB, the higher the burden of M. tuberculosis in the lung, the higher the intensity of pulmonary 67Ga citrate uptake. Serial 67Ga-scintigraphy examinations are helpful in evaluations of the effectiveness of anti-TB therapy when assessments based on chest radiography are difficult.
Keywords: lung • nuclear medicine • radiography • scintigraphy • tuberculosis
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Gallium-67 scanning has therefore been recommended as a complementary diagnostic tool when in a patient whose chest radiography conveys equivocal information regarding the presence of pulmonary TB. For example, 67Ga imaging is indicated when a clinician cannot exclude that TB developed in the original pulmonary fibrotic site of a patient with chronic lung disease [5, 10], or in the lung of a patient with underlying AIDS, because considerable numbers of chest radiographs in this patient population tend to be atypical [11-13]. The accumulation of 67Ga citrate at inflammation sites results from both its direct uptake by the culprit bacteria and its indirect uptake in inflammatory tissue, which is mediated by lactoferrin [9]. Lactoferrin, a major constituent of leukocytes, is an iron-binding protein with a strong affinity for 67Ga citrate. In addition, chemotaxis and the increased blood supply and blood vessel permeability in inflammatory tissues enhance the availability of 67Ga citrate in these areas. On the basis of this rationale, 67Ga citrate uptake is theoretically more intensified when tissue inflammation is progressing; and waning or disappearing 67Ga citrate uptake in the inflammatory site can be anticipated when tissue inflammation improves.
To clinically maximize the utility of 67Ga scintigraphy in the evaluation of pulmonary TB, we performed a prospective study to assess the qualitative association between the intensity of pulmonary uptake of 67Ga citrate and the severity of the lung inflammation, reflected by the burden of pulmonary Mycobacterium tuberculosis, which was presumably in proportion to semiquantitation of acid-fast bacillus (AFB) in the sputum. In this study, serial paired sputum-AFB semiquantitation and 67Ga scintigraphy in synchronized assessment in patients receiving anti-TB therapy were collected for analysis. Because of repeated measurements in a longitudinal study, the result will disclose whether 67Ga scintigraphy is potentially applicable in the follow-up evaluation of therapeutic responses in patients with pulmonary TB.
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Before initiation of anti-TB therapy, all enrolled patients had their sputum collected for acid-fast staining and culture for M. tuberculosis, and all underwent a baseline 67Ga-scintigraphy assessment. Anti-TB drugs prescribed for these patients included isoniazid, rifampicin, ethambutol, and pyrazinamide. Two subsequent evaluations on a 3-month basis (e.g., the second assessment in the third month and the third assessment in the sixth month) were scheduled, at which chest radiography, 67Ga scintigraphy, semiquantitation of sputum acid-fast staining, and sputum culture for M. tuberculosis were performed in every enrolled patient unless stated otherwise.
Radiographic, 67Ga-scintigraphic, and microbiologic evaluations arranged in the same chronologic order were regarded as a synchronized assessment. Patients entered in analysis were those with pulmonary lesions that were ultimately microbiologically proven to be pulmonary TB, and those whose pulmonary lesions found during the evaluation process to be the result of causes other than M. tuberculosis were withdrawn from the study.
Semiquantitation of AFB in Sputum and Identification of M. tuberculosis
The burden of M. tuberculosis in the lungs of the included
patients was reflected by the semiquantitations of AFB microscopically
identified in sputum, which were stratified as follows: AFB (-), when AFB were
absent in more than 100 high-power field (HPF [x1,000 magnifications]);
AFB (+), when one to nine AFB were found in 100 HPF; AFB (++), when one to
nine AFB were found in 10 HPF; and AFB (+++), when more than one AFB were
found in every HPF. Sputum specimens collected for acid-fast staining were
simultaneously sent for culture for M. tuberculosis using the
Löwn-stein-Jensen medium and Middle-Brook 7H11 medium (both from Becton
Dickinson).
Radiogallium Assessment and Grading of Pulmonary Uptake of 67Ga Citrate
At each radiogallium assessment, a patient was injected with 3 mCi (111
MBq) of 67Ga citrate, and the scanning was performed 2 days later
using a dual-headed gamma camera (Varicam, GE Healthcare) equipped with a
medium-energy, parallel-hole collimator. Images were obtained under the
conditions of 500 K counts per image and 20% window settings for the three
main energy peaks of 67Ga (93, 185, and 296 keV) in a 128 x
128 matrix.
Interpretation of 67Ga scintigraphy was performed by a radiologist without the knowledge of the results of the semiquantitation of sputum AFB of the patient in question. A higher 67Ga citrate uptake in the lung than that in soft tissue of the shoulder was regarded as a positive 67Ga scan. Positive 67Ga citrate scans were further graded as follows [14]: grade 1, uptake was less than that in the liver; grade 2, uptake was equal to that in the liver; and grade 3, uptake was more than that in the liver. Grade 0 refers to a negative 67Ga citrate scan. The differences in the spatial extent of pulmonary TB delineated by chest radiography and 67Ga-scintigraphy were assessed. The relationship of the findings in 67Ga scintigraphy, chest radiography, sputum bacteriology, and clinical response to anti-TB therapy at different stages of treatment courses of all patients was analyzed.
Statistics
The burden of pulmonary M. tuberculosis (reflected by
semiquantitation of AFB in sputum) and grading of 67Ga citrate
uptake in the lung at each synchronized assessment in every patient were
regarded as a paired variable. Generalized estimating equations (GEEs) were
used to assess the correlation of the burden of pulmonary M.
tuberculosis with the grading of 67Ga citrate uptake in the
lung [15]. The results of
semiquantitation of AFB in sputum were converted to corresponding numeric
ordinal variables, and AFB (-) was converted to 0 in statistical analyses
using SAS Proc Genmod. Odds ratios were obtained from the odds (GEE approach)
in favor of higher pulmonary 67Ga uptake in a differing score of
semiquantitation of sputum AFB. Linear trend for pulmonary 67Ga
citrate uptake corresponding to varied pulmonary M. tuberculosis
burden was assessed using contrast analysis of their odds ratios. A two-tailed
p value ± 0.05 was considered statistically significant. All
statistical analyses were performed using SAS software (version 9, SAS
Institute).
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As for the first paired 67Ga scintigraphy-chest radiography study, nine patients (30%) had the extent of 67Ga citrate uptake compatible with the sketches of the abnormalities suggestive of pulmonary TB on their chest radiographs, and 11 (36.7%) had the extent of 67Ga citrate uptake beyond the sketched counterparts on their chest radiographs, whereas six (20%) were negative at 67Ga scintigraphy. The 67Ga scintigraphy detection of abnormalities beyond those disclosed by chest radiographs included hila, mediastinum, bone, liver, stomach, nasopharynx, and more extending lung parenchyma, which subsequently disappeared in either the second or third assessment of the involved patients.
Characteristic changes in radionuclide uptake in serial 67Ga scintigraphy in one of these patients are shown in Figure 1A, 1B, 1C. The sensitivity of 67Ga scintigraphy in detecting pulmonary TB at enrollment was 80%. Among the six patients with a negative 67Ga scan at their first assessments, except for one young patient who had radiographically diffused pulmonary miliary lesions, all were elderly individuals, and two of these elderly patients had cavitations over their upper lobes seen on chest radiography. Underlying diabetes mellitus was found in two patients and hypertension in another two. The demographic and clinical characteristics of patients with an initial negative 67Ga citrate uptake are summarized in Table 2.
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At the second assessments (3 months after anti-TB therapy), 16 (64%) of 25 patients with initial positive acid-fast staining sputum each were found to have a negative AFB conversion and regression on chest radiography. Thirteen of these 16 patients had negative 67Ga scintigraphy and the other three had decreased intensities of 67Ga citrate uptake. The 26 patients who completed the scheduled serial assessments at the sixth month were eventually cured of their pulmonary TB. Of these 26, 22 each received 6 months of anti-TB therapy, and four (patients no. 5, 8, 9, and 15 in Table 1) each underwent at least 9 months of anti-TB therapy that was tailored by the chest physicians on the basis of their clinical, radiographic, and microbiologic responses. Detailed information on the results of initial and subsequent paired sputum acid-fast staining-67Ga-scintigraphy assessments performed every 3 months in the 30 included patients is shown in Table 1.
The semiquantitation of sputum AFB and the grading of 67Ga uptake in paired assessments are summarized in Table 3 and Figure 2. Logistic estimates of pulmonary 67Ga uptake in differing scores of sputum AFB semiquantitation and odds ratios of 67Ga uptake in the lung are shown in Table 4. The pulmonary 67Ga uptake increased in proportion to the higher score (indicating higher pulmonary M. tuberculosis burden) of sputum AFB semiquantitation (p = 0.009, for trend).
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All patients but one in our series who had an initial negative 67Ga scintigraphy were elderly; the single young individual had a pulmonary radiographically miliary pattern suggestive of a disseminated TB concurrently involving extrapulmonary sites [18, 19]. Aging-inherent waning immunity may in part account for the poor inflammatory reaction over the infection site; two of these six patients also had underlying diabetes mellitus, which might further deteriorate their immunity, and of note, two other patients had cavitated pulmonary TB. Cavitation is reflective of an aggravated pulmonary TB and perhaps a severely compromised immunity of the host [20].
Cavitation in pulmonary TB allows M. tuberculosis organisms to sequester themselves in a poorly perfused insulated lung space, which may lead to a negative 67Ga citrate uptake [9]. The improvement of immunity in a host with pulmonary TB and originally negative 67Ga scanning may subsequently convert to positive 67Ga scintigraphy [21]. Unfortunately, the two elderly patients in this series with radiographic cavitations had a persistent negative 67Ga scintigraphy in three consecutive assessments.
The limitations of our study are that the immunocompromise of the included patient was not specifically measured at the molecular level, although the relationship between immunoincompetence and poor pulmonary 67Ga citrate uptake resulting from the host's impaired inflammatory response was previously observed in similar patient populations [9, 16-19].
Theoretically, the intensity of 67Ga citrate uptake is in proportion to the severity of tissue inflammation, which, at least in part, parallels the burden of M. tuberculosis at the affected sites [7]. The compatibility of our study to the theoretic rationale implies that 67Ga scintigraphy can be applicable in serial evaluations of the therapeutic effectiveness against pulmonary TB. Although wholebody 67Ga citrate imaging has been widely used in the detection of extrapulmonary TB, some disadvantages exist. For example, extrapulmonary anatomic sites are subject to a higher incidence of infection with causes other than M. tuberculosis, and 67Ga citrate uptake is nonspecific to inflammation due to TB; furthermore, comparatively higher normal 67Ga tracer uptake is observed in the liver and bowel [22].
Indium-labeled WBC (111In-WBC) scanning is a potential alternative to 67Ga scintigraphy in detecting a focus of infection when resorting to radiopharmaceutical diagnostic imaging; however, the inconvenience and expense of labeling leukocytes with 111In hampers the widespread use of 111In-WBC scanning [23]. Although 18FFDG PET is a promising technique for diagnosing infection and inflammation, its specific role in diagnosing TB has not yet been established; the limited availability and expensive cost are shortcomings of FDG PET [24]. As a result, 67Ga citrate scintigraphy remains a widely used technique for radiop-harmaceutical diagnostic imaging.
The scenarios in which serial 67Ga scintigraphy evaluations may potentially be useful include, first, pulmonary TB in patients with chronic lung disease or AIDS, in whom unequivocal evaluation of the response to anti-TB treatment is difficult because of the masking effect that results from either chronic pulmonary fibrotic change or immunocompromise-associated poor inflammatory reaction [5, 10, 16, 17, 21]; and second, assessments of appropriate durations for treatments with different anti-TB regimens, especially for treatment with new anti-TB drugs.
In conclusion, our study indicates that the intensity of 67Ga citrate uptake is significantly in proportion to the burden of M. tuberculosis in the lung of patients with pulmonary TB, and serial 67Ga scintigraphy is helpful in evaluating the effectiveness of anti-TB therapy when assessments based on chest radiography are difficult.
Acknowledgments
We thank C. Y. Lin for her assistance with statistics.
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